Cholesterol‐Derived Mannosylated Polypeptide‐Formed Lipid Nanoparticles for Efficient in Vivo mRNA Delivery

Apr 21, 2025Small methods

Cholesterol-Based Sugar-Coated Lipid Particles for Efficient mRNA Delivery in Living Organisms

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Abstract

CPSM-LNP and CM/CPSM-LNP demonstrate preferential accumulation in lymph nodes compared to commercial ALC-LNP.

Mannosylated lipid nanoparticles are designed to enhance delivery of mRNA vaccines to immune cells.
The combination of cholesterol-derived mannopolypeptides and other lipids creates stable nanoparticles that can target antigen presenting cells.
CPSM-LNP and CM/CPSM-LNP show effective mRNA delivery in dendritic cells and mice.
These mannosylated nanoparticles could improve the efficacy of mRNA vaccines by increasing their presence in lymph nodes.

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Effective delivery of lipid nanoparticles (LNPs)-based mRNA vaccines to antigen presenting cells (APCs) is important for eliciting potent immune responses. However, most LNPs-based mRNA vaccines usually suffer from insufficient accumulation in APCs due to the lack of active targeting capability, leading to the limited efficacy and the need for high injection dose. In this study, a series of cholesterol-derived mannopolypeptide (CPSM) and cholesterol-conjugated mannose (CM) derivatives is synthesized to prepare mannosylated LNPs for efficient mRNA delivery. The co-assembly of CPSM and/or CM is demonstrated with ionizable lipid, helper lipid, and cholesterol into LNPs provides the colloidal stability of LNPs, and endows LNPs the ability to target APCs. The leading mannosylated LNPs including CPSM-LNP and CM/CPSM-LNP exhibit efficient mRNA transfection ability in dendritic cells and mice. Specifically, CPSM-LNP and CM/CPSM-LNP show preferential accumulation in the lymph nodes compared with commercial ALC-LNP from Pfizer/BioNTech's COVID-19 mRNA vaccine formulation. This study presents a straightforward yet effective strategy to synthesize cholesterol-derived mannopolypeptides and prepare mannosylated LNPs for successful in vivo mRNA delivery.

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Cholesterol‐Derived Mannosylated Polypeptide‐Formed Lipid Nanoparticles for Efficient in Vivo mRNA Delivery

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